The present invention relates to cyclic urethane compounds, and pharmaceutical compositions thereof, useful in treating humans or other mammals with cardiac arrhythmia and/or cardiac fibrillation.
The cyclic urethane compounds disclosed herein are active as antifibrillatory and antiarrhythmic agents. The present compounds exhibit broad efficacy against cardiac arrhythmia and fibrillation and can be satisfactorily applied to substantially alleviate and/or prevent arrhythmia and fibrillation. In addition, said compounds exhibit a lower incidence of some of the undesirable side effects than do many of the conventional antiarrhythmic therapies. An additional benefit of the compounds described herein is that they exhibit both antifibrillatory and antiarrhythmic activity; conventional therapies generally do not exhibit efficacy as antifibrillatory agents. See e.g. Coplen, S. E. et al., "Efficacy and Safety of Quinidine Therapy for Maintenance of Sinus Rhythm after Cardioversion--A meta-analysis, Circulation, Vol. 82, pp. 1106-1116,(1990); and Echt, D. S. et al., "Mortality and Morbidity in Patients receiving Ecainide, Flecainide, or Placebo: The Cardiac Arrhythmia Suppression Trial", N. Enql. J. Med., Vol. 324, pp. 781-788 (1991), both hereby incorporated by reference herein.
In a healthy, structurally-sound heart, the precise, sequential electrical activation, then deactivation, of the entire cardiac muscle that occurs unerringly with each beat is characterized as normal cardiac rhythm. Arrhythmias are characterized as occurrences of abnormal electrical activity that can interfere with normal cardiac rhythm. The abnormal electrical activity can interfere with the initiation of, and/or the uniform spread of, the electrical wave (i.e. depolarization followed by repolarization of the cardiac muscle) that triggers the heart to contract. The disruption of the smooth, cyclical process of cardiac function associated with normal cardiac rhythm by the existence of arrhythmias is, in some instances, life-threatening.
Arrhythmias range in severity from relatively benign (consisting of asymptomatic and infrequent premature ventricular complexes [PVCs]) to life-threatening (consisting of ventricular fibrillation, and sustained ventricular tachyarrhythmia). For an excellent review of arrhythmias and an overview of antiarrhythmic therapy, see, e.g. Bigger, Thomas J., "Antiarrhythmic Treatment: An Overview", American Journal of Cardiology, Vol. 53, pp. 8B-16B, Feb. 27, 1984; Goldstein, S. "Toward a New Understanding of the Mechanism and Prevention of Sudden Death in Coronary Heart Disease, Circulation, Vol. 82 (1), pp. 284-88 (1990); and Woosley, R. L., "Antiarrhythmic Drugs" Annu. Rev. Pharmacal. Toxical. Vol. 31: pp. 427-455, (1991), all hereby incorporated by reference herein. Life-threatening arrhythmias are noted as a leading cause of death worldwide. For instance, it is estimated that sudden cardiac death resulting from ventricular fibrillation kills approximately 400,000-600,000 people in the United States each year. U.S. Department of Health and Human Services (1985) NCHS Monthly Vital Statistics Report 33:8-9.
Arrhythmias are generally classified into two types: 1) Supraventricular Arrhythmias (for example, atrial fibrillation and flutter) and 2) Ventricular Arrhythmias (for example, ventricular tachyarrhythmia and ventricular fibrillation and flutter).
Supraventricular arrhythmias are generally not life-threatening. Individuals with these arrhythmias may experience a wide range of symptoms, from slight to severe intensity. These individuals may feel the physical sensation of missed beats, extra beats, and/or flutter, may occasionally feel slightly light-headed or dizzy, and may have shortness of breath and/or chest pain. Since this situation is, in fact, generally not life threatening, more aggressive therapies such as conventional antiarrhythmic drugs are sometimes not prescribed, because the side effects usually associated therewith may not be acceptable for a non-life-threatening condition. However, the the cyclic urethane compounds described herein are generally much better tolerated than many of the conventional, currently available antiarrhythmics; therefore, they would be an acceptable therapy for many patients suffering from supraventricular arrhythmias and would substantially alleviate the discomfort these individuals experience.
Ventricular arrhythmias, on the other hand, are potentially much more serious and have been classified into three groups: 1) benign; 2) prognostically-significant (potentially lethal);
and 3) life threatening (lethal). See, e.g. Morganroth, J. and Bigger, J. T., "Pharmacological Management of Ventricular Arrhythmias after the Cardiac Arrhythmia Suppression Trial," Amer. J. Cardiol. Vol. 65, pp. 1497-1503, 1990, (hereinafter Morganroth & Bigger), hereby incorporated by reference herein.
Individuals with benign arrhythmias exhibit very low risk of sudden death, cardiac scarring, and heart disease. Benign ventricular arrhythmias are relatively common and account for approximately 30% of all ventricular arrhythmias. Id. Benign arrhythmias, such as premature ventricular complexes (PVCs), pose minimal risks to individuals and rarely require antiarrhythmic therapy. However, the PVCs may be of a frequency or complexity, or are associated with sufficiently alarming symptoms, so that individuals experiencing them do not respond to reassurance that the arrhythmias and symptoms are not dangerous. They also may not respond to more conventional treatment (e.g. beta-blockers). In these cases, treatment with the compounds described herein will likely be beneficial to these individuals.
Prognostically-significant arrhythmias are associated with some additional clinical presentation of cardiac disease, such as mild heart failure, ischemic symptoms, and/or cardiac scarring. It has been stated that approximately 65% of all ventricular arrhythmias are prognostically significant. See, e.g. Morganroth & Bigger, at 1497.
Patients with life-threatening arrhythmias may present with syncope (sudden loss of consciousness--usually fainting--associated with insufficient brain perfusion), cardiac arrest, heart failure, and/or myocardial ischemia, in the presence of structural heart disease. Life-threatening arrhythmias are relatively uncommon; probably less than 10% of the individuals suffering from arrhythmias suffer from a lethal form. See Morganroth & Bigger at 1497. However, due to the life-threatening nature of lethal ventricular arrhythmias and the severity of symptoms, they must be aggressively treated.
The cyclic urethane compounds described herein are efficacious against cardiac fibrillation and supraventricular and ventricular arrhythmias. In addition, the said compounds exhibit less of the side effects which have come to be tolerated in traditional antiarrhythmic therapy, for lack of acceptable alternate therapies. For example, many current therapies cause pulmonary toxicity, cardiac depression, and neurologic effects not specific to cardiac tissue. For an excellent discussion of the side effects associated with conventional antiarrhythmic therapies see, Bigger, J. T. and Hoffman, B. F., "Antiarrhythmic Drugs" in Goodman and Gilman's The Basis of Pharmacological Therapeutics, 8th edition, ed. A. G. Gilman, pp. 840-873, New York: Pergamon; and Woolsey, R. L. "Antiarrhythmic Agents", in The Heart, ed. J. W. Hurst, pp. 1682-1711. New York: McGraw-Hill (1990), both incorporated by reference herein.
In addition, the compounds described herein are readily bioavailable, which facilitates treatment by oral administration, and therefore greatly facilitates patient compliance. In addition, the compounds described herein are relatively inexpensive to manufacture, and they exhibit a high degree of stability in oral dosage forms.